Treatment with cancer drugs such as bortezomib has been associated with adverse events (AE) such as peripheral neuropathy (PN). Bortezomib-induced peripheral neuropathy typically occurs within the first courses of treatment with bortezomib and generally reaches a plateau at cycle 5 (Windebank & Grisold (2008) J. Peripher. Nerv. Syst. 13:27-46). Primarily, a small fiber and painful, axonal, sensory distal neuropathy is produced. The associated pain has a mean rating of 7.8 (on scale of 0 for no pain and 10 for worst imaginable pain) (Cata et al. (2007) J. Pain 8:296-306).
Bortezomib-induced pain is associated with three major fiber types (Aβ, Aδ and C caliber primary afferent fibers) in sensory nerves. An electrophysiologic nerve conduction study shows low amplitude of sensory action potential (distal, sensory, axonal neuropathy) (Richardson et al. (2006) J. Clin. Oncol 24:3113-3120). Conduction studies are consistent with primary or secondary demyelination process due to primary myelin-Schwann cell damage or degeneration of fast-conducting fibers (demyelination neuropathy noted in ulnar nerves) (Badros et al. (2007) Cancer 110: 1042-1049).
Mitochondrial and endoplasmic reticulum damage in addition to other factors may play a key role in bortezomib-induced peripheral neuropathy development in humans. Bortezomib activates the mitochondrial-based apoptotic pathway (Pei et al. (2004) Clin. Cancer Res. 10:3839-3852). Bortezomib may also play a role in disregulation of neurotrophins as evidenced by inhibition of NF-kB activation which has been shown to block transcription of nerve growth factor (NGF) mediated neuron survival (NGF induces differentiation and survival of sensory nerve cells) (Landowski et al. (2005) Cancer Res. 65:3828-3836).
It has been observed that bortezomib-induced peripheral neuropathy is predominately sensory. Patients with pre-existing signs of peripheral neuropathy may experience worsening peripheral neuropathy during treatment. Dose reduction resulted in improvement or resolution of peripheral neuropathy in 51% of patients with >Grade 2 PN in a phase 2 multiple myeloma study. Dose discontinuation resulted in improvement or resolution of peripheral neuropathy in 73% of patients discontinuing due to Grade 2 peripheral neuropathy or who had >Grade 3 peripheral neuropathy in a phase 2 multiple myeloma study.
Adverse responses to drugs constitute a major medical problem. To the extent that some of these adverse events are due to genetically encoded biochemical diversity among patients in pathways that effect drug action, the identification of variances that are predictive of such effects will allow for more effective and safer drug use. Thus, there is a need for biomarkers useful for identifying patients most at risk for bortezomib-induced neuropathy.